COVID-19 prophylaxis with immunoglobulin Y (IgY) for the world population: The critical role that governments and non-governmental organizations can play

several key properties, including a broad, robust, and variant-insensitive specificity, a simple and low-cost manufacturing process able to be used in low-resource settings, and stability with a long product life.

Governmental and non-governmental organizations should accept the challenge of anti-SARS-CoV-2 IgY development, despite the difficult route to commercial economic benefit.

PASSIVE IMMUNIZATION AND IMMUNOGLOBIN Y
Passive immunization with parenterally-given immunoglobulin G has a long history of effectiveness in preventing human infectious diseases caused by viruses [12]. Intranasal antibody prophylaxis has also been an especially effective means to protect against multiple viral pathogens [13]. Egg yolk antibodies called immunoglobulin Y (IgY) have been effective in preventing disease transmission when given prophylactically in both animal models and human clinical settings of viral and bacterial diseases (as reviewed in [14]).
IgY antibodies, which do not activate the human complement system or bind the Fc receptor on immune cells, are known for their favourable safety profile. Overall, available data suggest that IgY antibodies given by non-parenteral administration do not have unwanted off-target pro-inflammatory effects and are non-toxic to humans, allowing for potential clinical applications in diverse populations and diseases [14,15], including the elderly, the immunocompromised, and children. IgY prophylaxis may also be valuable when used with personal protective equipment for individuals at increased risk of infection.
IgY is cheap, simple, and fast to produce [16]. The high yield of IgY per egg, rapid scale-up, and mass production at low cost (including in low-resource settings) make this a very practical approach as a potential passive immunization against COVID-19. After a laying hen is immunized with recombinant antigen, eggs can be produced for 8-10 months at a rate of nearly one egg a day, each containing up to 100 mg of IgY. This yield can be up to five times higher when using specific-pathogen-free hens. IgY purification can be achieved by a simple water extraction process (Figure 1). We reported a step-by-step protocol for IgY purification in lowand middle-income countries using inexpensive, readily available materials in place of costly, specialized laboratory equipment and chemicals [17].

CONCLUSION
The global death toll from COVID-19 is now over six million, with estimates of excess deaths associated with COVID-19 at least double that figure during 2020 and 2021 alone [18]. The impact of COVID-19, including long COVID, is sobering, regardless of a country's economic status. In the United States, COVID-19 was the third leading cause of death (after heart disease and cancer) in 2021 and has caused the biggest drop in life expectancy since World War II [19]. Similar patterns have emerged in Europe [19]. Urgent calls for global COVID-19 "vaccine-plus" approaches have been made [20]. Yet, global inequities that demand novel and local approaches to treatments are most critical for low-and middle-income countries. For example, the Africa Centres for Disease Control and Prevention (CDC) cautioned that less than 1% of vaccines on the continent are manufactured locally, which precludes an efficient response to pandemics such as COVID-19 [21].
IgY from hens immunized with inactivated SARS-CoV-2, recombinant S protein, or N protein can neutralize the virus in vitro. Additionally, intranasally administered IgY antibodies directed to the receptor-binding domain of SARS-CoV-2 protected hamsters [10] and mice [22] challenged with the virus. We have recently re-ported that anti-SARS-CoV-2 neutralizing hen IgY, which is effective against several variants of concern in vitro that indicate a diverse and polyclonal response, had an excellent safety profile in humans without systemic absorption when used as intranasal drops in a phase 1 clinical trial [23]. The large-scale, local, ecologically sound, and animal-friendly technology of production and affordability of high-titer anti-SARS-CoV-2 IgY make it attractive for further studies to provide global protection in resource-limited environments. Furthermore, because current variants of concern have significantly reduced vaccine effectiveness, and future variants may cause potentially more serious and lethal diseases, clinical trials can now define whether IgY may be a rapid means to halt the pandemic more broadly than is presently possible.
Public and private funding of COVID-19 drug and vaccine development has been significant. Moreover, a wide range of actions to enable more equitable global access to COVID-19 therapeutics has been proposed. Yet, a difficult route to economic benefit has likely hampered the commercial development of IgY therapeutics by industry. This is a call to action for private, governmental, for-profit, and non-profit sectors to take on the challenge.